Non-Alcoholic Steatose Hepatitis (NASH)

 

Physiopathology

Non-Alcoholic Steatose Hepatitis (NASH) is an aggressive form of Non-Alcoholic fatty liver disease (NAFLD) which is characterized by abnormal fat storage (steatosis) and inflammation in the liver eventually leading to advanced fibrosis and finally cirrhosis and hepatocellular carcinoma. Fat cells chronic inflammation driven by overnutrition, inactivity and aging leads to insulin resistance and hepatic steatosis which then induce NASH and eventually cirrhosis.

 

Current treatment

The management of the disease first includes hygienic recommendations such as physical activity and healthy diet. The medicinal management consists in preventing the metabolic disorders associated with NASH such as obesity, diabetes and hyperlipidemia but no molecule is specifically dedicated to treat this condition. Bariatric surgery, through induction of major weight loss, can also have a positive effect on liver histology in obese patients with NASH.

Despite the above management, NASH can eventually worsen, and cirrhosis of the liver can develop making liver transplantation the only effective treatment.

 

Solution brought by ALF-5755

HIP/PAP protects the liver against severe intoxication or inflammation by promoting the survival of hepatocytes both in vitro and in vivo (Lieu et al. 2005, Simon MT et al. 2003).

 

ALF-5755 is efficiently protecting the liver on several aspects:

 

– It has proven its efficacy in a mouse model with induced acute liver failure : A single dose of ALF-5755 in this mouse model was associated with an overall mice survival correlated with a decreased liver cells mortality and an increased cell proliferation (Moniaux et al. 2011).

– In a mouse model of insulin resistance, ALF-5755 decreases the steatosis score associated with the liver pathology in this mouse model (unpublished data)

 

Cancer

 

 

Physiopathology

The physiopathology of cancers is diverse and complex since cancer can be on different type and located in different body area. However, all types of cancer are characterized by an expansion of abnormal cells derived from normal tissue and invasion of adjacent tissues. Insulin resistance and hyperinsulinemia have been shown to be involved in the development of several cancer types including digestive, breast and colorectal cancers.

 

Current treatment

Cancer management is various depending of the cancer type but generally include medicinal treatment and eventually surgery, radiotherapy, hormonal therapy, biological therapy or immunotherapy. All of these therapies display drawbacks for patients since they can be very aggressive or contraindicated depending on the health of the patients. Therefore, there is a need for safer and effective alternatives.

 

Solution brought by ALF-5755

HIP/PAP administration lowered tumor progression and potentiates the effect of anti-cancer treatment. Accordingly, ALF-5755 treatment slows down the progression of tumor in rat model of colorectal cancer and decreases the tumor size in a mouse model of primary mammary cancer. The same effects are observed in vitro with beneficial effect of ALF-5755 on mammary cancer cell line (MCF7) and on pancreatic cancer cell lines (PANC1).

 

Alzheimer’s disease (AD)

 

 

Physiopathology

AD is a neurodegenerative disease characterized by cognitive and behavior impairments. The hallmarks of the disease are the presence of amyloidosis deposits and degenerative neurofibers mainly in the hippocampus -area implicated in the memory- but also in other area of the cerebral cortex involved in thinking and decision making. Several risk factors are linked to dementia in AD including aging, obesity, insulin resistance and oxydative stress .

 

Current treatment

Currently, no molecule can treat Alzheimer’s disease. Some drugs modulating neurotransmitters are used to slow down the progression of dementia but with a relative efficacy and a bad tolerance. Consequently, the management of AD is mainly nonmedicinal.

 

THAC addresses Alzheimer’s disease by targeting insulin resistance. The company established a collaboration with the laboratory of Dr. K. Nash to establish a proof of concept on the efficacy of ALF-5755 on animal models of Alzheimer’s disease